APETx2 is selective and reversible blocker of acid-sensing ion channel 3 (ASIC3) (ic50 values are 63 and 175 nm for homomeric rat and human asic3 channels). It also inhibits nav1.8 and nav1.2 channels (ic50 values are 55 and 114 nm respectively). It shows analgesic effect on acid induced and inflammatory pain.
CAT No: R0883
CAS No:713544-47-9
Synonyms/Alias:APETx2;713544-47-9;H-Gly-DL-xiThr-DL-Ala-DL-Cys(1)-DL-Ser-DL-Cys(2)-Gly-DL-Asn-DL-Ser-DL-Lys-Gly-DL-xiIle-DL-Tyr-DL-Trp-DL-Phe-DL-Tyr-DL-Arg-DL-Pro-DL-Ser-DL-Cys(3)-DL-Pro-DL-xiThr-DL-Asp-DL-Arg-Gly-DL-Tyr-DL-xiThr-Gly-DL-Ser-DL-Cys(2)-DL-Arg-DL-Tyr-DL-Phe-DL-Leu-Gly-DL-xiThr-DL-Cys(1)-DL-Cys(3)-DL-xiThr-DL-Pro-DL-Ala-DL-Asp-OH;APETx2 TFA;APE-4472-S;NDB54447;AKOS024458355;DA-70987;Gly-Thr-Ala-Cys-Ser-Cys-Gly-Asn-Ser-Lys-Gly-Ile-Tyr-Trp-Phe-Tyr-Arg-Pro-Ser-Cys-Pro-Thr-Asp-Arg-Gly-Tyr-Thr-Gly-Ser-Cys-Arg-Tyr-Phe- Leu-Gly-Thr-Cys-Cys-Thr-Pro-Ala-Asp;
APETx2 is a peptide toxin originally isolated from the sea anemone Anthopleura elegantissima, recognized for its potent and selective inhibitory activity against acid-sensing ion channels (ASICs), particularly the ASIC3 subtype. As a disulfide-rich peptide, APETx2 exhibits a stable tertiary structure that facilitates specific interactions with ion channel proteins, making it a valuable molecular tool in neurophysiological and pain signaling research. Its unique sequence and structural properties have positioned it as an important reagent for scientists investigating ion channel pharmacology, peptide-receptor interactions, and the molecular basis of sensory transduction.
Ion Channel Pharmacology: APETx2 serves as a highly selective probe for the functional characterization of acid-sensing ion channels, especially ASIC3, which is implicated in pain perception and mechanotransduction. By acting as a reversible inhibitor, it enables researchers to dissect the physiological and pathophysiological roles of ASICs in neuronal tissues. Its use in electrophysiological assays, such as patch-clamp recordings, allows for precise modulation of channel activity, thereby facilitating the identification of ASIC-dependent signaling pathways in both in vitro and ex vivo systems.
Pain Pathway Elucidation: The peptide is extensively employed in preclinical research to elucidate the molecular mechanisms underlying nociception and inflammatory pain. APETx2's ability to selectively block ASIC3 provides a means to differentiate between ASIC-dependent and independent components of pain signaling in sensory neurons. This specificity is particularly valuable in studies aiming to map the contribution of individual ion channel subtypes to pain hypersensitivity, hyperalgesia, and related phenomena. Its application helps clarify the complex interplay between extracellular pH changes and neuronal excitability in various pain models.
Peptide Structure-Activity Relationship Studies: Due to its well-defined disulfide-bonded scaffold, APETx2 is frequently utilized in structure-activity relationship (SAR) analyses to investigate the determinants of peptide-ion channel interactions. Researchers employ synthetic analogues and site-directed mutagenesis of the peptide to map critical residues involved in binding and inhibition. These studies advance the understanding of peptide-based modulation of ion channels and support the rational design of novel peptide ligands with enhanced selectivity or altered pharmacological profiles.
Tool for Drug Discovery: The specificity and potency of APETx2 make it an indispensable reference compound in the screening and validation of new ASIC inhibitors. In drug discovery pipelines, it is used as a benchmark to assess the efficacy, selectivity, and mechanism of action of novel small molecules or biologics targeting ASICs. Its inclusion in high-throughput screening assays and secondary validation steps ensures that candidate compounds are evaluated against a well-characterized standard, thereby increasing the reliability of early-stage pharmacological studies.
Biochemical and Biophysical Research: Beyond its direct applications in neurobiology, APETx2 is also utilized in broader biochemical and biophysical research contexts. Its stable peptide framework and ion channel targeting properties render it a useful model for studying peptide folding, stability, and membrane protein interactions. Researchers leverage it to develop and refine analytical techniques such as surface plasmon resonance, nuclear magnetic resonance spectroscopy, and X-ray crystallography, aiming to elucidate the molecular details of peptide-receptor engagement and the conformational dynamics of disulfide-rich peptides.
The structural characteristics of APETx2 are compared with that of PcTx1, another effector of ASIC channels but specific to the ASIC1a subtype and to APETx1, a toxin structurally related to APETx2, which targets the HERG potassium channel.
Solution structure of APETx2, a specific peptide inhibitor of ASIC3 proton-gated channels
ASICs appear to be key mediators of inflammatory pain. ASIC antagonists and antisense oligonucleotides reduced both thermal and mechanical hyperalgesia in a rat model of inflammatory pain, highlighting the utility of selective pharmacological agents for studying ASIC channel function. Unfortunately, only two selective ASIC inhibitors have been discovered. The tarantula toxin PcTx1 is a specific blocker of homomeric ASIC1a channels, whereas the sea anemone peptide APETx2 blocks homomeric ASIC3 and ASIC3-containing heteromeric channels. PcTx1 is potently analgesic in mouse models of inflammatory and neuropathic pain, while APETx2 abolishes acid-induced pain in rats. Thus, APETx2 is an invaluable tool for study of ASIC3 channels.
Chemical synthesis and folding of APETx2, a potent and selective inhibitor of acid sensing ion channel 3
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